In the past 25 years, a new family of viruses capable of causing debilitating immunodeficiency diseases (acquired immunodeficiency diseases, AIDS) in mammals has emerged as a serious global health threat. These viruses, which include the human immunodeficiency virus (HIV), and its simian and feline counterparts (simian immunodeficiency virus (SIV), and feline immunodeficiency virus (FIV)) are composed of single-stranded RNA, and can be transmitted though contact with blood, or through sexual intercourse. Individuals infected with these viruses exhibit a profound collapse of their immune system, and the consequent presentation of secondary opportunistic infections, such as Candida albicans oesophagitis, mucocutaneous herpes simplex infection, Pneumocystis carinii-induced pneumonia, cryptosporidial enteritis, etc.
Without treatment, immunodeficiency viral infection is highly lethal. Indeed, AIDS is the leading cause of human death (Chaisson, R. E., “HIV becomes world's leading infectious cause of death,” Hopkins HIV Rep. 1999 July; 11(4):1). In certain parts of the world, such as sub-Saharan Africa, at least 10% of all adults are believed to be infected with HIV, with the prevalence in many capital cities believed to be 35% or more (Gottlieb, S., “Gap in HIV infection widens,” BMJ 1998;317:11). In the United States, an estimated 800,000 to 900,000 people are currently infected with HIV, with approximately 40,000 new infections occurring each year. Of the more than 700,000 individuals in the United States who were infected with HIV as of December 2000, 58% have died.
Human immunodeficiency virus-1 infects and damages or destroys several types of cells, most importantly helper/inducer (CD4+) lymphocytes. In the majority of infected persons, the loss of CD4+ lymphocytes leads to a progressive reduction in both cell mediated and antibody mediated immunity. Early during infection most adults are asymptomatic, but after several years many develop symptoms representing a moderate degree of immune suppression. Eventually, most of these individuals become susceptible to the life-threatening opportunistic infections and cancers which define the acquired immunodeficiency syndrome (Cohn, J. A., “Virology, immunology, and natural history of HIV infection,” J. Nurse Midwifery 1989 September-October; 34(5):242-52).
The main cellular target of HIV infection is the CD4+ T cell. CD4+ T-cell titers in most people decline relentlessly throughout the course of HIV infection. In late stages of the disease a change occurs in the phenotype of the virus from non-syncitium-inducing (NSI) isolates of HIV-1 which dominate in primary infection to strains of HIV which are cytopathic and syncitium-inducing (SI) (Rowland-Jones, S., “Long-term Non-progression in HIV Infection Clinico Pathological Issues,” J. Infection (1999) 38, 67-70). This change in phenotype also correlates to a change in the chemokine co-receptors used by the virus for entry into CD4+ cells (Veugelers, P. J., et al., “Differences in the Time form HIV Seroconversion to CD4 Lyphocyte Endpoints and AIDS in Cohots of Homosexual Men.” AIDS 1993: 7: 1328-1329).
In addition to changes in phenotype, different strains of HIV also target different receptors. G protein-coupled receptors serve as co-receptors in the infection process of human immunodeficiency virus type-1 (HIV-1), type-2 (HIV-2), and SIV. CXC-CKR, CXCR5/BLR1, is a novel co-receptor for HIV-2, but does not appear to function as a receptor for HIV-1 or SIV (Kanbe K., et al., “A CXC chemokine receptor, CXCR5/BLR1, is a novel and specific co-receptor for human immunodeficiency virus type 2,” Virology 1999 Dec. 20;265(2):264-73).
HIV is believed to have evolved from its simian counterpart, SIV. The two viruses are genetically very similar, and are transmitted the same way. The disease induced by the SIVsm subtype is, however, remarkably similar to human AIDS. However HIV only causes AIDS in humans, and SIV only causes AIDS in monkeys. The SIV family is, however, a diverse group of viruses that vary considerably in pathogenesis and virulence in their natural host species (macaques). The pathogenesis of SIVsm (and other viruses) in macaques offers an relevant animal model for pathogenesis and vaccine trials, the interactions of these viruses in their natural host, and virus-, or host-specific effects (U.S. Pat. No. 6,017,536 (Barney, et al.; Hirsch V M, et al., “Pathogenic diversity of simian immunodeficiency viruses,” Virus Res 1994 May;32(2): 183-203).
Feline immunodeficiency virus (FIV, formerly called feline T lymphotropic lentivirus (Pederson et al., Science, 235:790 (1987)), has been identified in the United States, the United Kingdom (Harbour et al., Vet Rec, 122:84 (1988)), Japan (Ishida et al., Jpn J Vet Sci, 50:39 (1988)), Australia (Sabine et al., Aust Vet Practit, 18:105 (1988)), and New Zealand (Swinney et al., NZ Vet J, 37:41 (1989)). The virus appears to be spread by horizontal transmission, predominantly by bite wounds (Yamamoto et al., Am. J. Vet. Res., 8:1246 (1988); Friend et al., Aust. Vet J., 67:237 (1990). FIV is a typical retrovirus that preferentially replicates in feline T lymphoblastoid cells and is the causative agent of a cat disease with features similar to those of HIV-induced human AIDS (Pedersen, N., et al., Science 235: 790 (1987); U.S. Pat. No. 5,665,592 (Tompkins, et al.)). HIV-1 and FIV belong to the lentivirus subfamily of retroviruses, have similar morphology, protein composition, and reverse transcriptases (RT) that exhibit Mg2+-dependency (Pedersen, N., et al., Science 235: 790 (1987); Pedersen, N., et al., Vet. Immunol. Immunopathol. 21: 111 (1989)). Both HIV and FIV display tropisin for T lymphocytes and monocytes and are capable of inducing these cells to form syncytia. (Brunner, D., et al., J. Virol. 63: 5483 (1989); Gardner, M., et al. FASEB Journal 3: 2593 (1989)). FIV is reviewed by Willis, A. M. (“Feline leukemia virus and feline immunodeficiency virus,” Vet Clin North Am Small Anim Pract. 2000 September;30(5):971-86); Podell, M. et al. (“The feline model of neuroAIDS: understanding the progression towards AIDS dementia,” J Psychopharmacol. 2000;14(3):205-13); and Bogers, W. M. et al. (“Developments in preclinical AIDS vaccine efficacy models,” AIDS. 2000;14 Suppl 3:S141-51).
While the overall genetic organization of FIV is similar to that of HIV, the reduced complexity of FIV's regulatory open reading frames suggests that FIV may be closer to ungulate lentiviruses than to primate lentiviruses.
FIV infects both CD4+ and CD8+ T lymphocytes as well as feline B lymphocytes and inacrophages. In addition, the FIV cellular receptor does not appear to be mostly constituted by the feline CD4 differentiation antigen (Martinon, O., et al., “URA-INRA, Immunopathologie cellulaire et moleculaire (IPCM),” Vet Res 1993;24(2):151-8). U.S. Pat. No. 5,648,209, (Avrameas, et al.) describes the feline immunodeficiency virus (FIV), and the use of FIV peptide fragments as diagnostic reagents. A wide variety of symptoms are associated with infection by FIV, including abortion, alopecia, anemia, conjunctivitis, chronic rhinitis, enteritis, gingivitis, hematochezia, neurologic abnormalities, periodontitis, and seborrheic dermatitis. The immunologic hallmark of domestic cats infected with FIV is a chronic and progressive depletion of feline CD4+ peripheral blood lymphocytes, a reduction in the CD4:CD8 cell ratio and, in some cases, an increase in CD8-bearing lymphocytes. Cats with full blown Feline AIDS have an average life expectancy of no more than six months to a year. No effective treatment for FIV has yet been defined. U.S. Pat. No. 6,254,872 (Yamamoto) discusses FIV-vaccines. U.S. Pat. No. 6,228,608 (Young et al.) discusses the use of viral proteins as antigens to provide a therapy for FIV infection.
It is known that antiretroviral drugs can induce immunologic improvement in patients with acquired immunodeficiency syndrome (AIDS) and other manifestations of immunovirus infection. Significant progress has been made in the development of antiretroviral therapy (ART) to block retroviral transcription and assembly. Sixteen licensed antiretroviral drugs are in use that target HIV-1 proteins such as Vpr, Tat, Rev, Vif, Nef, Env, Gag, Vpu. Antiretroviral therapies include nucleoside analogues (NA), protease inhibitors, non-nucleoside reverse transcriptase inhibitors (NNRT1), nucleoside analogs, and combination therapies employing one or more of therapies listed above). Other strategies for inhibiting retroviral infection are discussed by Johnston, et al., 1993, Science 260, 1286-1293, and by Franzusoff, et al. (U.S. Pat. No. 5,691,183).
The use of alternative treatments and medicinal herbs has been suggested for the treatment of feline acquired immunodeficiency disease (see, e.g., Garlic, Goldenseal, Cats claw, Ambrotose, Acemannan (abstract of Aloe), Essaic Tea, Baypamun, Felovite II with Taurine, Immuplex/Livaplex/Thymex/Cataplex AC/Pneumotrophin PMG Echinacea C/Immuplex/Congaplex, Vitamin C, Colloidal silver, Co enzyme Q10, MGN-3, Flax Seed Oil, Vanilla flavoring, Liquid Chlorophyll, Ester-C powder, Bone Meal powder, Acidophilus powder, Beta Carotene, Parsley, Vitamin E, Brewers Yeast, thymus hormone, Melissa, Hypericum, Lomatium, Turmeric, and Momordica, (see, http://www.holisticat.com/felv arch.html;
http://www.listservice.net/wellpet/fiv.htm;
http://www.whiterosepath.com/bodysong/Fiv%20and%20FeLV.html;
http://www.walthamusa.com/walthamnavc/Wynn/Wynn.pdf). The use of alternative medicainents for FIV is discussed by Wynn, S. G. (“Integrative Approaches to Feline Viral Diseases.” http://www.walthamusa.com/walthamnavc/Wynn/Wynn.pdf).
An herbal formulation (“VS-C;” http://www.theherbsplace.com/vsc.html) is sold as a treatment for FIV. The ingredients of VS-C are: Dandelion Root, Purslane Herb, Indigo, Herb & Root (contains indirubin), Thlaspi, Buplburum Root, Scute Root, Pinellia Rhizome, Ginseng Root, Cinnamon Twig, and Licorice Root.
Despite such progress, no fully successful therapy for acquired immunodeficiency diseases has yet been identified. In light of the substantial morbidity and mortality associated with immunodeficiency virus infection, a need exists for improved therapies for treating viral-induced immunodeficiency disease and/or preventing the proliferation of immunodeficiency viruses. Despite the therapeutic advances made by antiretroviral therapies, problems of drug resistance, latent viral reservoirs, and drug-induced toxic effects that compromise effective viral control point to a need for new classes of anti-HIV drugs with different modes of action. (D'Souza, M. P., et al., “Current Eviidence and Future Directions for Targeting HIV Entry,” JAMA, Jul. 12, 2000—Vol. 284, No. 2) (Yarchoan R, et al., “The immunology of HIV infection: implications for therapy,” AIDS Res Hum Retroviruses 1992 June;8(6): 1023-31). The present invention is directed to such needs.